Device and method for accurate delivery of an active agent

ABSTRACT

Implantable delivery devices ( 1 ) for accurately controlling release of an agent therefrom and for preventing release of the agent during storage, prior to use. The devices include a reservoir ( 3 ) for storing the agent, a driving means for driving the agent from the reservoir ( 3 ) and a valving and control mechanism ( 10 ) which is positively actuatable between a closed configuration and an open configuration.

FIELD OF INVENTION

The present invention relates generally to implantable delivery devices,and more particularly to accurately controlling the delivery of an agentfrom a device, as well as preventing release of an agent from a deviceduring shelf storage.

BACKGROUND OF THE INVENTION

Controlled delivery of beneficial agents such as drugs in the medicaland veterinary fields has been accomplished by a variety of methods thatmay employ various types of drug delivery device. A range of exemplarydevices and methods are well described in “Encyclopedia of ControlledDrug Delivery” 1999, published by John Wiley & Sons Inc, edited by EdithMathiowitz. Drug delivery devices including an implantable device, whichdevice can be based on, for example, diffusive, erodible or convectivesystems, e.g., pumps, such as osmotic pumps, that may or may not beconnected to a catheter, biodegradable implants, electrodiffusionsystems, electroosmosis systems, vapor pressure pumps, electrolyticpumps, effervescent pumps, piezoelectric pumps, electrochemical pumps,erosion-based systems, electromechanical systems, liposomes, depots, ormicrospheres. Every containerized device requires an orifice of one sortor another, and such an orifice must address the particular needs ofdrug delivery in a certain situation, such as the need for low flowrate, steady, predictable flow rate and the need to keep the orificeclosed until flow is required.

One approach for delivering a beneficial agent involves the use ofimplantable diffusional systems. For example, subdermal implants forcontraception are descried by Philip D. Darney in Current Opinion inObstetrics and Gynecology, 1991, 3:470-476. Norplant.RTM. requires theplacement of 6 levonorgestrel-filled silastic capsules under the skin.Protection from conception for up to 5 years is achieved. The implantsoperate by simple diffusion, that is, the active agent diffuses throughthe polymeric material at a rate that is controlled by thecharacteristics of the active agent formulation and the polymericmaterial.

Another method for controlled prolonged delivery of a beneficial agentinvolves the use of an implantable osmotic delivery system. Osmoticdelivery systems are very reliable in delivering the beneficial agentover an extended period of time. The osmotic pressure generated by anosmotic pump also produces a delivery rate of the beneficial agent intothe body which is relatively constant as compared with other types ofdelivery systems.

In general, osmotic delivery systems operate by imbibing fluid from theoutside environment and releasing corresponding amounts of thebeneficial agent Osmotic delivery systems, commonly referred to as“osmotic pumps”, generally include some type of a capsule having wallswhich selectively pass water into an interior of the capsule whichcontains a water-attracting agent. The absorption of water by thewater-attracting agent within the capsule reservoir creates an osmoticpressure within the capsule which causes the beneficial agent to bedelivered from the capsule. The water-attracting agent may be thebeneficial agent delivered to the patient, however, in most cases, aseparate agent is used specifically for its ability to draw water intothe capsule.

When a separate osmotic agent is used, the osmotic agent may beseparated from the beneficial agent within the capsule by a movabledividing member or piston. The structure of the capsule is such that thecapsule does not expand when the osmotic agent takes in water. As theosmotic agent expands, it causes the movable dividing member or pistonto move, which in turn causes the beneficial agent to be dischargedthrough an orifice at the same volumetric rate that water enters theosmotic agent by osmosis.

Another method for controlled prolonged delivery of a beneficial agentinvolves the use of an implantable chemical or electrochemical deliverysystem. A controlled delivery device for holding and administering abiologically active agent includes a housing which encloses a displacingmember, a chemical or electrochemical cell that generates pressure, andmay include activation and control circuitry. The electrochemical orchemical cell generates gas within the housing, forcing the displacingmember against the beneficial agents contained within the housing andforcing the beneficial agents through an outlet port and into theenvironment of use at a predetermined rate.

The orifice in any of the above devices controls the interaction of thebeneficial agent with the external fluid environment. The orifice servesthe important function of isolating the beneficial agent from theexternal fluid environment, since any contamination of the beneficialagent by external fluids may adversely affect the utility of thebeneficial agent. For example, the inward flux of materials of theexternal fluid environment due to diffusion or osmosis may contaminatethe interior of the capsule, destabilizing, diluting, or otherwisealtering the beneficial agent formulation. Another important function ofthe orifice is to control or limit diffusional flow of the beneficialagent through the orifice into the external fluid environment.

In known delivery devices, these functions have typically been performedby flow moderators. A flow moderator may consist of a tubular passagehaving a particular cross sectional area and length. The cross sectionalarea and length of the flow moderator is chosen such that the averagelinear velocity of the exiting beneficial agent is higher than that ofthe linear inward flux of materials in the external environment due todiffusion or osmosis, thereby attenuating or moderating back diffusionand its deleterious effects of contaminating the interior of the osmoticor diffusion pump.

In addition, the dimensions of the flow moderator may be chosen suchthat the diffusive flux of the beneficial agent out of the orifice issmall in comparison to the convective flux. One problem with flowmoderators, however, is that the passage may become clogged orobstructed with particles suspended in the beneficial agent or in fluidfrom the external environment. Such clogging may be reduced oreliminated by increasing the diameter of the passage to 5 mil or more,for example. However, this increase results in a greater rate ofdiffusion of the beneficial agent out of the pump. A correspondingincrease also occurs in the back diffusion of the external fluid intothe pump which may contaminate the beneficial agent and adversely affectthe desired delivery rate of the beneficial agent. Tolerances duringfabrication also frequently dictate that the orifice diameter be greaterthan about 5 mils.

Systems with a long straight flow moderator are also impractical forimplantation applications because they increase the size of the implantsignificantly making the system difficult to implant.

Leakage of the beneficial agent from the pump or device, prior toimplanting the same, may occur due to pressure changes in the reservoircontaining the beneficial agent caused by changes in temperature of theenvironment that the pump is being stored in. Loss of beneficial agentto the environment through evaporation is another common occurrence tovarying degrees during the storage or shelf life of various implantablepumps.

Another problem associated with pressure driven implantable drugdelivery devices is known as the burst effect, wherein, due to thermalexpansion of a drug or other beneficial agent upon removing theimplantable device from a room temperature, shelf environment andimplanting it into an environment at body temperature, an initial volumeor bolus of the drug or beneficial agent is delivered from the devicewhich is often much larger than a predetermined measured dose calledfor. This phenomenon can be a critical problem, causing severe damage oreven death to the patient in the worst scenarios.

Current flow modulators also cause separation of beneficial agents whichcontain suspensions of bioactive macromolecules (proteins, genes, etc.).When such suspensions pass along a restriction in current flowmodulators, the suspension separates and the delivery concentration ofbioactive macromolecules varies.

Additionally, if a drug formulation is allowed to sit in a deliveryoutlet channel during storage, then precipitation of solutes out ofsolution (due to evaporation and surface effects) may cause the deliveryoutlet channel to become blocked with precipitated solute.

The above problems are particularly acute when the drug to be deliveredis highly potent, when the volume to be delivered is small, and whendelivery is done aver a prolonged period of time.

Thus, there is a need for methods and devices that solve the problems ofkeeping the system closed until needed, controlling drug burst due todifferential thermal expansion of the drug and the container, reducingprecipitation of drug causing blockage of the outflow channel, andproviding a uniform, even and predictable flow of drug out of the drugdelivery device. The current invention fulfills these needs.

SUMMARY OF THE INVENTION

The invention is a manually or positively actuated valve on the exitorifice of the reservoir of an implantable pumping device. The valveallows for the system to be closed during its shelf life and thusprevents the exit of fluid out of the reservoir of the system duringstorage. Prior to operation of the system, the valve is positivelyactuated (this can be a manual actuation performed by the user throughpushing, pulling, or turning a component of the valve) by the user.Examples of valve designs which incorporate each of the three mechanismsare disclosed in the attached figures.

The valve designs must contain several important features. The firstfeature is that the valve must allow room for thermal expansion of thecontents of the pump after it has been actuated. This is important so asto control the release of drug substance which is contained in the pumpdue to the increase of the temperature of the pump contents from roomtemperature to body temperature. The next feature which is important tothe valve is that it be positively or manually actuated so as to allowfor a fully patent outflow track or exit orifice once it is actuated.This is important so as to allow for even flow of the contents from thepump during operation. Systems which are spring loaded or which use thebuildup of pressure in the system as a means to actuate the valve havebeen shown to provide erratic pumping performance due to the buildup andrelieving of pressure in the pump reservoir during operation. A fullypatent orifice which is yielded from positive manual actuation of thevalve does not allow for this buildup and release of pressure on thereservoir and the subsequent erratic release of drug formulation whichresults. The next feature the valve needs to have is the ability to beproduced of substantially biocompatible materials if used in an implantapplication. In addition, the valve needs to be able to withstand thepressure buildup which occurs in the reservoir of the closed systemduring temperature and atmospheric pressure cycling of the system instorage.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the devices and methods as more fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more readily understood upon reading thefollowing detailed description in conjunction with the drawings, a briefdescription of which follows.

FIG. 1 illustrates a portion of a delivery device employing a flowcontrol arrangement according to the present invention in a position atwhich flow is prevented.

FIG. 2 illustrates the delivery device as in FIG. 1, but with the flowcontrol arrangement positioned to allow flow from the delivery device.

FIG. 3 illustrates a portion of a delivery device employing another flowcontrol arrangement according to the present invention in a position atwhich flow is prevented.

FIG. 4 illustrates a portion of a delivery device employing stillanother flow control arrangement according to the present invention in aposition at which flow is prevented.

FIG. 5 illustrates the delivery device as in FIG. 4, but with the flowcontrol arrangement positioned to allow flow from the delivery device.

FIG. 6 illustrates a portion of a delivery device employing a variationof the flow control arrangement shown in FIGS. 4-5, in a position atwhich flow is prevented.

FIG. 7 illustrates a portion of a delivery device employing a variationof the flow control arrangement shown in FIG. 1, in a position at whichflow is allowed.

FIG. 8 illustrates a portion of a delivery device employing stillanother flow control arrangement according to the present invention, ina position at which flow is prevented.

FIG. 9 illustrates a portion of a delivery device employing a flowcontrol arrangement which is rotatable to allow or prevent flowtherethrough.

FIG. 10 illustrates a portion of a delivery device employing a variationof the flow control arrangement shown in FIG. 9 with the flow controlarrangement positioned to allow flow from the delivery device.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Before the present flow control arrangements, delivery devices andmethods of controlling flow are described, it is to be understood thatthis invention is not limited to particular mechanisms described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit the stated range. Where the stated range includes one orboth of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are now described. All publications mentioned herein areincorporated herein by reference to disclose and describe the methodsand/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “e” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aring” or “an O-ring” includes a plurality of such rings or O-rings andreference to “the flow path” includes reference to one or more flowpaths and equivalents thereof known to those skilled in the art, and soforth.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

DEFINITIONS

The term “agent” includes water, an electrolyte, any physiologically orpharmacologically active substance or substances, or combinationsthereof. An agent may further optionally include other pharmaceuticallyacceptable carriers and/or additional ingredients such as antioxidants,stabilizing agents, permeation enhancers, etc.

The term “reservoir” refers to a chamber or containment space within adelivery device for storing an agent to be delivered from the deliverydevice.

The term “flow path” refers to the pathway taken by an agent as it isdispensed from a reservoir of a delivery device to the outside of thedelivery device.

The present invention encompasses methods and devices for providing animplantable drug delivery device having a closed system reservoir thatsubstantially prevents leakage or evaporation of the contents of thereservoir during the shelf life of the device. The present inventionalso accommodates for thermal expansion of the drug or beneficial agentas well as any driving media contained within the device which isexperienced upon a change of temperature of the environment in which thedevice resides. One example of such change in temperature is thatexperienced when a device is moved from a “shelf” environment ofapproximately room temperature, to a body temperature environment uponimplantation of the device into a human or animal patient. However,other significant temperature changes can occur, even during storage ofa device (i.e., during its shelf life). Such accommodation preventsdeleterious burst effects upon implantation of a device according to thepresent invention.

Referring to FIG. 1, an example of a drag delivery device 1 exhibitingall of the above described characteristics is shown. The device includesa housing or pump body 2 that houses a reservoir 3 for holding a drug orbeneficial agent to be delivered from the device 1. The driving forcefor driving drug out of the reservoir 3 and the device and to a deliverysite may be osmosis, diffusion, electrodiffusion, electroosmosis,electrochemical for example, although the present invention is notlimited only to implantable devices driven by these modalities, but mayalso include actively driven devices (e.g., motor-driven) for example,or any other membrane modulated device which delivers drug to atreatment site.

Housing or pump body 2 may be made of titanium for example, or otherrelatively rigid and biocompatible structural materials such as platinumalloys, tungsten, gold, medical grade stainless steel or other inertmetals or alloys, plastics such as polyethylenes, nylons, PETS etc.Housing 2 surrounds a reservoir 3 which is provided for containing adrug or beneficial agent to be delivered from device 1 to an environmentof use. At a lower end of device 1 (not shown), housing 2 furthercontains a piston or other driver, which separates the drug andreservoir 3 from another chamber that houses a driving mechanism for thedevice. As noted, the driving mechanism may be an osmotic pumparrangement, diffusion pump arrangement chemical or electrochemical pumparrangement, or other modality. Examples of some of these modalities canbe found in U.S. Pat. Nos. 5,169,383; 5,951,538; 5,567,287; 4,886,514;5,593,552; 5,538,605; 5,454,922; 5,707,499; and 5,855,761, for example,each of which is incorporated herein in its entirety, by referencethereto.

At the upper end of the device a valving and control mechanism 10 isfixed at least partially within housing 2 to form a closed systemreservoir 3 for storage of the device 1 and for controlled delivery ofdrug/beneficial agent upon actuation of the valving and controlmechanism 10. A bottom ring assembly is secured adjacent reservoir 3with a bottom end of the bottom ring assembly contacting thedrug/beneficial agent contained within reservoir 3. The bottom ringassembly in this example includes a valve seat member 12 fitted within abottom ring 16 and at least one O-ring 14 forming a seal between thevalve seat member 12 and inner walls of housing 2. Valve member 12 maybe formed of ultra high molecular weight polyethylene (UHMWPE), orpolyethylene, or other biocompatible polymer exhibiting sufficientstrength and low creep characteristics to serve as a valve seat withplunger 18 acting there against, e.g. (but not limited to):flouroelastomer (Viton™), high or low density polyethylene, linear lowdensity polyethylene etc.

The bottom ring assembly is press fit (e.g., with about 150 lbf in thisexample) or otherwise securely fixed within housing 2 so that the bottomof valve seat member 12 contacts the contents of reservoir 3. As thebottom ring assembly is positioned against the reservoir 3 any airexisting therebetween is drawn out by a removable vacuum line (notshown) inserted through valve neck 12 c, and the valve seat member ispositioned so that a meniscus 13 formed by the top of thedrug/beneficial agent forms at the top of bottom cone 12 d formed in thevalve seat member 12. Bottom cone 12 d acts to focus or funnel thedrug/beneficial agent into the valve neck 12 of valve seat member 12.

Bottom ring 16 is locked within shoulders 12 a,12 b of valve seat member12 to provide additional stability to the placement of the valve seatmember 2 and to provide integrity of the bottom ring assembly duringinsertion into housing 2. Bottom ring 16 may be formed of titanium, forexample, or other relatively rigid and biocompatible structuralmaterials such as platinum alloys, tungsten, gold, medical gradestainless steel or other inert metals or alloys, plastics such aspolyethylenes, nylons, PETS etc. and provides a superior anchoringfunction due to the larger area of surface contact between bottom ring16 and the inner walls of housing 2 (relative to the area of surfacecontact between valve seat member 12 and housing 2) and/or by makingbottom ring 16 to have a slightly larger outside diameter than thelargest outside diameter of valve member 12 so as to develop relativegreater compressive forces when inserted in housing 2. Interlocking withshoulders 12 a,12 b prevents movement of the valve seat member eitherupwardly or downwardly with respect to housing 2, thereby securelysituating it in contact with the drug or beneficial agent in reservoir3.

O-ring(s) 14 provide additional assurance that leakage/evaporation ofdrug(beneficial agent does not occur between the valve seat member12/bottom ring assembly and the housing 2. Bottom O-ring(s) 14 may bemade of VITON™ or any other biocompatible rubbers or polymers suitablefor performing the sealing function indicated, e.g. (but not limitedto): silicone rubber, butyl rubber, C-flex™, flouroelastomer, high orlow density polyethylene, linear low density polyethylene etc.

A top ring assembly is secured in the open end of housing 2 with abottom end of the top ring assembly abutting the top end of the bottomring assembly to complete the valving and control mechanism 10. The topring assembly in this example includes a plunger 18, fitted within a topring 20 and at least one O-ring 22 forming a seal therebetween. Asplunger 18 is designed to slide within top ring 20, O-ring 22 may besituated between a pair of shoulders 18 a,18 b to maintain O-ring 22 inthe same position relative to plunger 18 as plunger 18 slides. Shoulders18 a,18 b maintain the relative position of O-ring(s) 22 whilepermitting O-ring(s) 22 to slide or roll along the inner walls of topring 20, all the while maintaining the seal between plunger 18 and topring 20.

Shoulder 18 a also abuts against shoulder 20 a of top ring 20 duringinsertion of the top ring assembly into device 1. Plunger 18 and topring 20 are dimensioned so that upon fitting into housing 2, theshoulder abutment 20 a,18 a ensures that the plunger seal 18 c ofplunger 18 is properly placed within the valve neck 12 c of valve 12where it seats with the valve, when the bottom end of top plug 20 abutsagainst the top end of bottom plug 16. The top ring assembly is securelypositioned within housing 2, by press-fitting (e.g., with about 50 lbf)or by other fluid and vapor tight method of securing, such thatreservoir 3 becomes a closed system for shelf storage. By press fittingthe components as described, the assembly 10 can withstand backpressures (i.e, pressures provide by the drug driven by the pumpingsystem) of up to about 5000 psi. Since most pumping systems are designedto back out at about 1000 psi this arrangement provides more than anadequate margin of safety. The seal formed between plunger seal 18 c andvalve neck 12 c forms a fluid and vapor tight seal, while O-ring(s) 22provide additional assurance that no leakage/evaporation ofdrug/beneficial agent leaks or evaporates between plunger 18 and topring 20 to the environment. Top ring 20 and plunger 18 may be made oftitanium, for example, or other relatively rigid and biocompatiblestructural material such as those described previously. Top O-ring(s) 22may be made of VITON™ or any other biocompatible materials describedabove for use in making O-ring 14.

A location groove 18 d is provided in plunger 18 to ensure properplacement of plunger 18 relative to top ring 20, which ultimatelyensures proper positioning and sealing of the plunger seal 18 c ofplunger in valve neck 12 c upon assembly. Since plunger 18 is slidablewith regard to top ring 20, it is possible that plunger 18 could beinadvertently depressed, or slid downwardly, at least partially relativeto top ring 20 during assembly. This could possibly result in distendingplunger seal 18 c below valve neck 12 c so that a proper seal for shelfstorage would not be formed. Location groove 18 d is formed at alocation along plunger 18 which ensures that, as long as location groove18 d is visible, it is assured that the plunger 18 is located withshoulder 18 a abutted against shoulder 20 a, or plunger 18 is at leasthigh enough relative to top ring 20 so that plunger seal 18 c will seatwith valve seat 12 in the valve neck 12 c.

By assembling both bottom and top ring portions as described above,valving and control mechanism 10 converts reservoir 3 to a closed systemreservoir, thereby sealing the contents of reservoir 3 (drug(beneficialagent) for shelf storage of device 1 and preventing leakage orevaporation of the drug/beneficial agent from device 1 during storageand as long as valving and control mechanism 10 is maintained in theconfiguration shown in FIG. 1.

When it comes time to implant device 1 or otherwise place it in anenvironment of use, valving and control mechanism is actuated to a useposition as shown in FIG. 2, thereby opening reservoir 3 to a flow paththat leads out of device 1 for delivery of drug/beneficial agent to theenvironment of use. In the example of FIGS. 1 and 2, plunger 18 isdepressed relative to housing 2 to a position where the top of plunger18 is substantially flush with the top end of top ring 20.Actuation/depression of plunger 18 requires about 3-4 lbf, for example,and once depressed, top O-ring 22 maintains the plunger in the depressedposition against forces of up to about 0.5 lbf. This actuation forcesplunger seal 18 c out of valve neck 12 c and into the volume defined bybottom cone 12 d, thereby breaking the seal formed between plunger seal18 c and the valve seat (i.e., valve neck 12 c) thereby opening a flowpath through the valve seat member 12 between valve neck 12 c andplunger 18. This flow path further connects with a space defined betweenthe plunger 18 and top cone 12 e formed in valve seat member, which inturn flows into channel 12 e that connects with top ring flow path 20 bformed in top ring 20 and bordered by the inner walls of housing 2. Theflow pathway thus defined forms a widely patent or open exit channelwhich allows the uniform flow of drug/beneficial agent from thereservoir 3 to the environment of use during the operation of thepumping system as it provides a driving force to the reservoir 3.

When describing the exit channel as “widely patent” it is meant that thechannel is clearly open and unobstructed with a continuous sizesufficient to allow clear, even and unobstructed flow of a fluidtherethrough. This is an important advantage of the present system overcertain other designs that employ a build-up of pressure within thedevice to force open a valve (such as a spring-loaded valve). Theproblem with such pressure-opened designs is that they become brieflyopen when the pressure inside has built up to a sufficient degree, butonce the pressure is released upon opening, the valve tends to shutagain, and although theoretical calculations would indicate that aconstant pressure would be reached to produce an even flow, this has notproved the case experimentally, such pressure release designs produce anuneven and/or intermittent flow that may be highly undesired whendelivering a potent drug.

In the example shown, top ring flow path is formed as a spiral pathway,which provides a relatively larger volume capacity than a straight flowpathway would, given the same cross-sectional dimensions of thepathways. The flow pathways described above (including top ring flowpath 20 b and the pathways connecting it to the drug/beneficial agent)provide a thermal expansion space or capacity for the drug/beneficialagent to flow into after actuation of the valving and flow controlmechanism (FIG. 2) to prevent a burst effect upon implantation of device1 into an organism or other environment of use having a significantlyhigher temperature that would cause the volume of the drug/beneficialagent to expand and thus drive an amount of drug/beneficial agent fromthe reservoir prior to any pumping action by the pumping mechanism Forexample, a drug formulation in a device as shown might expand by about 2microliters in a device 1 with a titanium housing 2 after stabilizationof the temperature of the device after having been moved from a roomtemperature environment to a human body temperature environment. In sucha case, the flow pathways would be designed to have a volume of about 3microliters so as to have an extra margin of safety to ensure that aburst of drug would not be initially delivered to the patient uponimplantation. Of course, the volumes described are only an example, andthe actual volume of the flow pathways for preventing burst will varydepending upon the total volume of the drug in the reservoir, the crosssectional area(s) of the flow pathways, the change in temperature fromthe first to the second environment, etc. Generally, however, the volumeof the flow pathways will be designed such that, upon thermal expansionof the drug/beneficial agent in the environment of use, thedrug/beneficial agent will extend about two thirds of the way along thelength of the top ring flow path 20 b.

FIG. 3 is a partial view of a drug delivery device 1 which employsanother example of a valving and flow control mechanism according to thepresent invention. Components that are the same or substantially similarin design and function to the counterparts described in the example ofFIGS. 1 and 2 are not described here. In this example, valve seat member12 may be formed of titanium or other similar rigid, biocompatiblematerial, since it does not function to form a seal with plunger 18 inthe storage position shown in FIG. 3, but must form a press fit with theinner walls of housing 2 that is substantially equivalent of thatprovided by both valve seat member 12 and bottom ring 16 in the exampleshown in FIGS. 1 and 2.

A septum or puncturable disk 24 overlays valve seat member 12 in aconforming manner and is sandwiched between valve seat member and topring 20 which is press fit into abutment with septum 24, at which timeseptum 24 effectively seals reservoir 3 forming a closed system suitablefor storage without leakage/evaporation of the drug/beneficial agentcontained within reservoir 3. Septum or puncturable disk 24 may be madeof silicone rubber, flouroelastomer, polyethylene, PET, or otherbiocompatible rubber, polymer or thin frangible metal that may bereadily punctured.

The top ring assembly is secured in the open end of housing 2 similarlyto that described above with the example of FIG. 1, with a bottom end ofthe top ring assembly abutting the septum and sealing it between the topring 20 and valve seat member 12. The top ring assembly in this exampleincludes a plunger 18, fitted within a top ring 20 and at least oneO-ring 22 forming a seal therebetween. The plunger 18 in this example,does not form a seal with the valve seat member 12, as that function isprovided by the septum 24. Although not shown, a location groove 18 dmay also be provided in plunger 18 of this example, to provide the samefunction as described above with respect to the example of FIGS. 1 and2.

Actuation of the valving and control mechanism 10 opens reservoir 3 to aflow path that leads out of device 1 for delivery of drug/beneficialagent to the environment of use. Actuation is performed by manually orotherwise positively depressing plunger 18 relative to housing 2 to aposition where the top of plunger 18 is substantially flush with the topend of top ring 20. Actuation/depression of plunger 18 drives a sharpend 18 i of plunger 18 through septum 24, thereby providing an openingthrough septum 24 and breaking the seal of the reservoir 3. A notch,groove, hollow, or other bypass feature 18 d is provided above the point18 i in a location that traverses the punctured septum 24 when plunger18 is in the depressed position, thereby providing a more patent or openflow path for the drug/beneficial agent between septum 24 and plunger18. The flow path continues on out to top ring flow path 20 b similarlyto that described above.

Turning to FIG. 4, a portion of a drug delivery device 1 is shown whichemploys a pull valve or a type of pulling action to actuate the valvingand flow control mechanism 10. In this example, valve seat member 12 issimilar to that in FIG. 3 in that it may be made of titanium or otherrigid biocompatible material and serves the functions of both the valveseat member and bottom ring of FIG. 1. An O-ring 14 is provided toprevent leakage/evaporation of drug/beneficial agent between valve seatmember 12 and the inner walls of housing 2. An elastomer valve seal 26(made from suitable materials e.g., but not limited to: flouroelastomer(VITON™), high or low density polyethylene, linear low densitypolyethylene etc) overlies the top surface of valve seal member 12 inconforming fashion to seal off reservoir 3, thereby making it a closedsystem for storage. A flow path 21 connecting valve neck 12 c with topring flow path 20 b can be clearly seen in FIG. 4, and is sealed offfrom valve neck 12 c in the closed position by valve seal 26.

Plunger 18 in this example may again be made of titanium or otherstructurally strong and rigid biocompatible material capable of exertinga force required for sealing with little or no distortion of the plungermaterial (eg: from about 2-5 lbf). Plunger 18 includes a blunt tip 18 ewhich ensures a directed force fit of valve seal 16 against the flowpaths and may even partially distort the valve seal 16 to assume aposition partially within valve neck 12 c as shown in FIG. 4.

Top ring 20 is similar to previous embodiments in that it contains topring flow path 20 b and in that it is press fitted or otherwise securelyfixed into housing 2, However, the top portion of top ring 20 isdesigned to contain plunger 18 and provides stops 20 c against whichupper shoulders of plunger 18 abut when valving and flow controlmechanism 10 is actuated, as shown in FIG. 5. Upon assembly, plunger 18is positioned in the closed position shown in FIG. 4. It can be lockeddown by means of a threaded plug which, when screwed into neck of thering (20), holds the plunger down. The plug could also be pressed intothe ring (20) like a simple non-threaded plug, and held there byfriction.

Actuation of mechanism 10, as opposed to earlier examples, is by pullingback on the plunger (18) to reposition plunger 18 so that shoulder 18 aabuts against stops 20 c, thereby opening reservoir 3 to the flowpathways 12 c, 21, 20 b, as shown in FIG. 5. FIGS. 4 and 5 do not showthe means by which the plunger (18) is pulled out, but such a means mayuse the elasticity of the valve seal 26 to push the plunger out and openthe valve. In such an embodiment, in the closed position, the plungerwould be pushed down against the elastic resistance of the valve sealand be held in place by a suitable device such as a pin or by a simplemortise and tenon arrangement (not shown) whereby the plunger isdepressed and rotated such that a tenon, projecting from the plunger 18,slides into a mortise grove, cut into the inner surface of the ring 20,to hold the plunger in place. When released, the force of the valve sealpushes the plunger back to its default (open) position. Another simpledesign for opening and closing the valve would be to use a screw threadbetween the plunger 18 and the ring 20. Alternatively a means forpulling out the plunger may be provided by a manually pullable tab orprotruding portion attached to the plunger, or may be provided by asimple lock-and-key type slot in the top of the plunger that would allowthe plunger to be pulled back using a very simple tool. During the pullback operation, elastomeric seal member 26, converts potential energy tokinetic energy to provide a driving force for the repositioning ofplunger 18. Additionally, this example has the capability of resealingreservoir 3 if desired. Resealing can be effectuated by pressing down onthe top ring 20 to return plunger 18 to the position shown in FIG. 4.Optionally, a locking mechanism (not shown) may be provided to lock theplunger in the open position shown in FIG. 5. Such a locking mechanismmay be passive and may employ the screw threads mentioned earlier.

FIG. 6 shows another example of a valving and control mechanism 10 whichactuates through an action of moving the plunger away from the valvesealing member 12 and elastomeric seal 26. In this instance, threads 28are provided between plunger 18 and top ring 20, so that plunger 18 maybe rotated or torqued to translate its position with regard to top ring20. Thus to close the mechanism FIG. 6), plunger 18 is rotated in eithera clockwise or counterclockwise fashion (depending upon the handednessof threads 28) to the position shown in FIG. 6 to exert a sealingpressure on elastomeric seal 26 and to force it to conform to top cone12 e of valve sealing member 12, thereby sealing off valve neck 12 c andreservoir 3 and converting reservoir 3 into a closed system for storage.

Seal member 26 is interlocked with plunger 18 at shoulders 18 f and 18 gby shoulder portions 26 a and 26 b, respectively, to ensure positivedirect movement of seal member with the movements of plunger 18 in bothdirections. A slot 18 h or other tool engaging configuration (e.g.,Phillips head slot, Allen receptacle, or the like) may be provided inplunger 18 for receiving a tool that may be used for rotating plunger18. Alternatively, an extension, or other grasping conformation (notshown) may be formed to extend from plunger 18 for manual rotationthereof.

The valving and control mechanism 10 of the device 1 partially shown inFIG. 7 functions similarly to that described above with regard to FIGS.1 and 2, and is shown in an open or actuated position. In this example,valve seat member 12 may be formed of titanium or other similar rigid,biocompatible material, since it forms a press fit with the inner wallsof housing 2 that is substantially equivalent of that provided by bothvalve seat member 12 and bottom ring 16 in the example shown in FIGS. 1and 2. Since plunger 18 is also formed of titanium or other similarrigid, biocompatible material, an O-ring 30 or other sealing member isfitted on plunger seal 18 c, to ensure a positive seal with valve neck12 c in the closed configuration. O-ring 30 may be situated between apair of shoulders 18 k, 18 l to maintain O-ring 30 in the same positionrelative to plunger seal 18 c as plunger seal 18 c slides with respectto valve neck 12 c.

FIG. 8 shows another example of a valving and flow control mechanism 10in a drug delivery device 1 (partially shown) which is actuated bypushing or depressing plunger 18 further into the device. In thisarrangement, valve seat member 12 is formed of titanium or other similarrigid and biocompatible material which can be press fit into housing 2.A bore 12 f is formed in valve seat member 12 for receiving a portion ofplunger 18 upon actuation of the valving and flow control mechanism 10.A flow path 12 g, which in this example is a spiral flow path, but neednot necessarily be (e.g. a straight flow path other configuration may beused), is provided in valve seat member 12 and formed with the innerwalls of housing 2. (The advantage of the spiral path is that it is easyto machine and that it provides an overall higher volume for the drugpath between the reservoir and the outside, thereby providing morestability (more “play”) in the system when filing and dealing withthermal expansion). Flow path 12 g connects a channel 12 h leading fromreservoir 3 with a channel 12 i leading to bore 12 f.

In the closed or storage configuration shown in FIG. 8, plunger 18extends from the upper end of device 1 and top ring 20. Although notshown, a location groove 18 d may also be provided in plunger 18 of thisexample, to provide the same function as described above with respect tothe example of FIGS. 1 and 2. Plunger 18 may be formed of titanium orother structurally substantial and rigid biocompatible material, exceptthe lower tip 18 j is formed of polyethylene, flouroelastomer, UHMWPE orother biocompatible polymer capable of forming an acceptable seal withvalve neck 12 c in the closed position. As shown, lower tip 18 j ismechanically interlocked with the titanium end of plunger 18 and may bemolded onto the titanium in this configuration. Additionally oralternatively, lower tip 18 j may be bonded to the titanium plunger endand/or further mechanically or chemically fixed as by screwing, gluing,melt bonding, or otherwise affixing it. An O-ring 32 or other sealingmember is provided between valve sealing member 12 and housing 2 toassure that no leakage out of the system or evaporation ofdrug/beneficial agent occurs between these two components.

In the closed position lower tip 18 j of plunger 18 seals with valveneck 12 c to prevent flow, leakage or evaporation of drug/beneficialagent beyond the flow pathways 12 h,12 g,12 i. Upon depressing plunger18 to actuate mechanism 10 in a manner as described above, lower tip 18j is repositioned in bore 12 f to a location intermediate of the flowpathways 12 h and 12 i. The frictional forces between lower tip 18 j andbore 12 f are sufficient to maintain the plunger in the open position,being capable of withstanding forces of up to about 0.5 lbf, forexample. This action opens the flow pathways 12 h,12 g,12 i to flowpaths 21 and 20 b and thus to the exterior of device 1 thereby openingreservoir 3 for delivery of drug/beneficial agent to the environment ofuse.

FIG. 9 is another example of a valving and control mechanism 10 which isrotationally actuable in a drug delivery device 1. In this example,valve seat member 12 may be formed as a biocompatible polymer plug, outof polyethylene, UHMWPE or other biocompatible polymer having adequatestructural rigidity along with a capability for forming an adequate sealwith housing 2 and other titanium or structurally rigid components inthe mechanism 10. Top ring 20 is press fit or otherwise securely fittedin housing 2 and abuts against valve seal member to assist inmaintaining the position thereof. A top cap 34 which may be formed oftitanium or other structurally rigid, biocompatible material is securelyfixed to valve seat member within top ring 20. Fixation may be bygluing, heat welding or other mechanical or chemical means of fixation.Additionally, cap 34 may be mechanically interlocked with valve seatmember with regard to rotational movements about the longitudinal axis Lof device 1, to ensure positive rotational positioning of valve seatmember 12 when cap 34 is rotated. Although not shown, cap 34 may have aslot or other tool engaging configuration (e.g., Phillips head slot,Allen receptacle, or the like) for receiving a tool that may be used forrotating cap 34, similar to that described above with regard to plunger18 (FIG. 6). Alternatively, an extension, or other grasping conformation(not shown) may be formed to extend from plunger 18 for manual rotationthereof.

Valve seat member 12 is provided with a bore 12 f that leads into theinterior of the lug body of valve seat member 12 and connects reservoir3 with a selectable flow path 12 j. Selectable flow path 12 j extendsradially outward from bore 12 f to the exterior or outer circumferenceof valve seat member 12. Actuation from the off or closed position tothe actuated, on or “use” position shown in FIG. 9, is effected byrotation of cap 34 which in turn rots valve seat member 12 along withit, until selectable flow path 12 j aligns with a flow path or hole 20 dthat extends through top ring 20 and connects with top ring flow path 20b that leads to the exterior of the device at 20 e. In this way, an openor patent flow path 12 f,12 j,20 d,20 b,20 e is established betweenreservoir 3 and the environment of use.

This example allows the valving and control mechanism to be shut off orsealed, even after actuating, if desired, by reverse rotation (orfurther rotation in the same direction) to position selectable low path12 j out of alignment with hole 20 d. Optionally, the mechanism 10 maybe provided with a stop (not shown) to prevent over rotation of thevalve seat member 12 in the same direction of rotation once alignmenthas been reached during actuation. Additionally or alternativelyoptional (also not shown) a locking mechanism may be provided to lockthe device in the actuated configuration, to prevent inadvertent totalor partial closure of the flow path during use.

FIG. 10 shows an example of a valving and flow control mechanism 10, inan actuated position, in a drug delivery device 1 (partially shown)which is similar to the mechanism 10 shown in FIG. 9. In this example,however, bore 12 f connects with a bore 34 a in top cap 34 which furtherhas a selectable flow path 34 b extending radially (and in this casesubstantially perpendicularly, although not necessarily so) from bore 34a. Thus, in this example, top cap 34 is selectively rotatable foralignment of selectable flow path with flow path 12 j in valve seatmember 12, and valve seat member 12 is fixed within housing 2 (i.e.,does not rotate with the rotation of cap 34, nor does it translate).Flow path 12 j is connected to a flow path 12 l which leads to theexterior of valve seat member, by flow path 12 k extending between thesurfaces of valve seat member 12 and top ring 20. Flow path 12 lconnects with top rig flow path 20 b that leads out of the device 1 at20 e.

Similar to the example described and shown in FIG. 9, this exampleallows the valving and control mechanism 10 to be shut off or sealedeven after actuating, if desired, by reverse rotation (or furtherrotation in the same direction) of cap 34 to position selectable flowpath 34 b out of alignment with path or channel 12 j. Optionally, themechanism 10 may be provided with a stop (not shown) to prevent overrotation of cap 34 in the same direction of rotation once alignment hasbeen reached during actuation. Additionally or alternatively optional(also not shown) a locking mechanism may be provided to lock the devicein the actuated configuration, to prevent inadvertent total or partialclosure of the flow path during use.

Additionally, cap 34 may be mechanically interlocked with valve seatmember with regard to rotational movements about the longitudinal axis Lof device 1, to ensure positive rotational positioning of valve seatmember 12 when cap 34 is rotated. Although not shown, cap 34 may have aslot or other tool engaging configuration (e.g., Phillips head slot,Allen receptacle, or the like) for receiving a tool that may be used forrotating cap 34, similar to that described above with regard to plunger18 (FIG. 6). Alternatively, an extension, or other grasping conformation(not shown) may be formed to extend from plunger 18 for manual rotationthereof.

While the present invention has been described with reference to thespecific embodiments thereof it should be understood by those skilled inthe art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe present invention

1. An implantable device for accurate delivery of an agent, said devicecomprising: a housing (2) including a reservoir (3) for containing theagent; a valving and control mechanism (10) fitted at least partiallywithin said housing (2) and capable of assuming an open configurationand a closed configuration, wherein said valving and control mechanism(10) closes off said reservoir (3) when in said closed configuration,thereby preventing leakage of the active agent during storage in saiddevice; and wherein said valving and control mechanism (10) opens saidreservoir (3) to a flow path when in said open configuration, therebypermitting controlled delivery of the active agent.
 2. The device ofclaim 1, wherein said flow path has sufficient capacitance toaccommodate thermal expansion of the agent due to a change intemperature from room temperature to a patient body temperature and uponchanging said valving and control mechanism (1) from said closedconfiguration to said open configuration.
 3. The device of claim 1,wherein said valving and control mechanism (10) is positively actuatablebetween said closed configuration and said open configuration.
 4. Thedevice of claim 3, wherein said valving and control mechanism (10) ismanually actuatable.
 5. The device of claim 1, further comprising meansfor applying a driving force to the agent in said reservoir to drive theagent through the flow path and out of the device when said valving andcontrol mechanism are in said open configuration.
 6. The device of claim5, wherein said means for applying a driving force is selected from thegroup consisting of osmotic pumps, diffusion pumps, electrodiffusionpumps, electroosmotic pumps, and electrochemical pumps.
 7. The device ofclaim 5, wherein said means for applying a driving force comprises anactively driven device.
 8. The device of claim 5, further comprising adriver separating said means for applying a driving force from theagent.
 9. The device of claim 8, wherein said driver comprises a piston.10. The device of claim 3, wherein said valving and control mechanism(10) is actuated from said closed configuration to said openconfiguration by pushing an actuation portion thereof.
 11. The device ofclaim 3, wherein said valving and control mechanism (10) is actuatedfrom said closed configuration to said open configuration by pulling anactuation portion thereof.
 12. The device of claim 3, wherein saidvalving and control mechanism (10) is actuated from said closedconfiguration to said open configuration by rotating an actuationportion thereof.
 13. The device of claim 3, wherein said valving andcontrol mechanism (10) is further positively actuatable from said openconfiguration back to said closed configuration.
 14. The device of claim1, wherein said valving and control mechanism (10) comprises a valveseat member (12) peripherally sealed with respect to said reservoir anda plunger (18) adapted to slide with respect to said valve seat member(12) said valve seat member having an opening therethrough a includingvalve neck (12 c) adapted to seat with a portion (18 c) of said plunger(18) when said valving and control mechanism is positioned in saidclosed configuration, and wherein upon sliding said plunger to push saidportion (18 c) out of said valve neck, said valving and controlmechanism (10) is in said open configuration and said reservoir isopened to the flow path via said valve neck (12 c).
 15. The device ofclaim 14, wherein said valve seat member (12) is contained within alower ring (16) abutting said housing (2), said device furthercomprising an upper ring (20) abutting said lower ring (16), saidplunger (18) being slidably positioned within said upper ring (20) andsaid flow path extending between said housing (2) and said upper ring(20).
 16. The device of claim 15, wherein said flow path spirals aroundsaid upper ring (20).
 17. The device of claim 1, wherein said valvingand control mechanism (10) comprises a valve seat member (12)peripherally sealed with respect to said reservoir (3) and having apassageway extending therethrough for connecting said reservoir (3) withthe flow pathway, a septum (24) overlaying said passageway and sealingoff the reservoir (3) when said device is in said closed configuration;and a plunger (18) adapted to slide with respect to said valve seatmember (12) and to puncture said septum (24) upon pushing said plungerto pierce said septum (24) wherein said valving and control mechanism(10) assumes the open configuration and the reservoir (3) is therebyopened to the flow pathway.
 18. The device of claim 17, furthercomprising an upper ring (20) fitted within said housing (2), saidplunger (18) being slidably positioned within said upper ring (20) andsaid flow path extending between said housing (2) and said upper ring(20).
 19. The device of claim 18, wherein said flow path spirals aroundsaid upper ring (20).
 20. The device of claim 1, wherein said valvingand control mechanism (10) comprises a valve seat member (12)peripherally sealed with respect to said reservoir (3) and having apassageway extending therethrough for connecting said reservoir (3) withthe flow pathway, a valve seal (26) overlaying said passageway andsealing off the reservoir (3) when said device is in said closedconfiguration; and a plunger (18) adapted to slide with respect to saidvalve seat member (12) and to compress said valve seal (26) against saidvalve seat member (12) to seal off the reservoir (3) when said valvingand control mechanism (10) is in said closed configuration; and wherein,upon pulling said plunger (18) away from said valve seal (26), saidvalve seal (26) opens said flow path to said reservoir (3) wherein saidvalving and control mechanism (10) assumes the open configuration. 21.The device of claim 20, further comprising an upper ring (20) fittedwithin said housing (2), said plunger (18) being slidably positionedwithin said upper ring (20) and said flow path extending between saidhousing (2) and said upper ring (20).
 22. The device of claim 21,wherein said flow path spirals around said upper ring (20).
 23. Thedevice of claim 20, wherein said plunger (18) is pulled away bytranslating said plunger (18).
 24. The device of claim 20, wherein saidplunger (18) is pulled away by rotating said plunger (18).
 25. Thedevice of claim 1, wherein said valving and control mechanism (10)comprises a valve seat member (12) peripherally sealed with respect tosaid reservoir (3) and having a passageway connecting said reservoir (3)with a peripheral opening in said valve seat member (12); a top ring(20) surrounding a top portion of said valve seat member (12) and fittedwithin said housing (2), wherein said valve seat member (12) isrotatable with respect to said top ring (20), said top ring (20) furtherhaving an opening extending through a wall thereof and connecting withsaid flow path extending between said top ring (20) and said housing(2); wherein, upon rotation of said valve seat member (12) so that saidvalving and control mechanism assumes said open configuration, saidperipheral opening aligns with said opening extending through the wallof said top ring (20), thereby connecting said reservoir (3) with saidflow path.
 26. The device of claim 1, wherein said valving and controlmechanism (10) comprises a valve seat member (12) peripherally sealedwith respect to said reservoir (3) and a cap (34) arranged for rotationwith respect to said valve seat member (12), said valve seat member (12)having a bore (12 f) fluidly connecting said reservoir (3) with said cap(34) and a peripheral opening (12 j) fluidly connecting said cap withsaid flow path; said cap (34) having a passageway (34 a,34 b) fluidlyconnecting with said bore (12 f) and extending peripherally out of saidcap (34), wherein, upon rotation of said cap (34) so that said valvingand control mechanism (10) assumes said open configuration, saidpassageway (34 b) aligns with said peripheral opening (12 j), therebyconnecting said reservoir (3) with said flow path.
 27. A method ofstoring an agent in an implantable delivery device substantially leakfree, and of controllably delivering the agent from the device, saidmethod comprising the steps of: providing a delivery device having ahousing (2) surrounding a reservoir (3) containing the agent; means fordriving the agent from the reservoir (3); and a valving and controlmechanism (10) adjacent the exit orifice of the reservoir and beingpositively actuatable between a closed configuration, in which the agentis prevented from being delivered from the reservoir, and an openconfiguration, in which the agent is allowed to pass from the reservoir(3) through a flow path and out of the device; positioning the valvingand control mechanism (10) in the closed configuration during storage ofthe device, to prevent outflow of the agent; and actuating the valvingand control mechanism (10) to assume the open configuration to allow theagent to flow out of the reservoir.
 28. The method of claim 27, furthercomprising: providing sufficient volume capacitance in the flow path toprevent a burst effect release of the agent from the device, due tothermal expansion of the agent, upon actuating the valving and controlmechanism (10) from the closed configuration to the open configuration.